Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the world's population. It is characterized by inflammation and cellular proliferation in the synovial lining of joints that can ultimately result in cartilage and bone destruction, joint deformity and loss of mobility. RA usually causes problems in several joints at the same time, often in a symmetric manner. Early RA tends to affect the smaller joints first, such as the joints in the wrists, hands, ankles and feet. As the disease progresses, joints of the shoulders, elbows, knees, hips, jaw and neck can also become involved. Unlike other arthritic conditions that only affect areas in or around joints, RA is a systemic disease which can cause inflammation in extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs and muscles.
RA is associated with pain, deformity, decreased quality of life, and disability, which in turn affect patients' ability to lead a normal and productive life. Recent studies have shown that 5 years after the onset of the disease, approximately one third of patients with RA are no longer able to work, and within 10 years, half of the patients have substantial functional disability (A. Young et al., Rheumatology, 2007, 46: 350-357). Consequently, RA imposes an important economic burden on society. Considerable data also suggest that RA is associated with lowered life expectancy.
Although RA has been extensively studied, the etiology and pathogenesis of the disease remain incompletely understood. Factors that may increase the risk for RA include: sex of the individual (women are 2 to 3 times more likely than men to develop the disease); age (RA occurs more commonly between the ages of 40 and 60, although it can also strike children, teenagers and older adults); genetics (RA was found to be strongly associated with the inherited tissue type Major Histocompatibility Complex (MHC) antigen HLA-DR4—more specifically DRB1*0401 and DRB1*0404); and smoking (RA is about 4 times more common in smokers than non-smokers).
There is currently no reliable cure for RA. Treatment is essentially directed towards relieving pain, reducing inflammation, and stopping or slowing joint damage and bone destruction. The current therapeutic approach is to prescribe disease-modifying antirheumatic drugs (DMARDs) early in the condition, as RA patients treated early with such drugs have better outcomes, with greater preservation of function, less work disability, and smaller risk of premature death. Recent advances in the understanding of the pathophysiology of RA have led to the development of new DMARDs, called biological response modifiers. Biological DMARDs are designed to target and block the action of certain key cells or molecules, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), T-cells, and B-cells, involved in the abnormal immune reaction associated with RA. In comparison with traditional DMARDs, the biological agents have a much more rapid onset of action and can offer better clinical response with effective long-term prevention of joint damage (J. K. D. de Vries-Bouwstra et al., Rheum. Dis. Clin. North Am., 2005, 31: 745-762).
Since irreversible joint destruction can be prevented by intervention at the early stages of the disease, early diagnosis of RA is important. However, definitive diagnosis of RA can be difficult. Immunologic tests that can be performed for the diagnosis of RA include, in particular, measurement of the levels of rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Serological testing for RF is complicated by moderate sensitivity and specificity, and high rates of positivity in other chronic inflammatory and infectious diseases (T. Dorner et al., Curr. Opin. Rheumatol, 2004, 16: 246-253). Anti-CCP antibody testing is particularly useful in the diagnosis of RA, with high specificity, positivity early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, a negative result in anti-CCP antibody testing does not exclude RA.
Therefore, there is a great need for new biological markers of RA. In particular, biomarkers that would allow reliable diagnosis and monitoring of the early stages of the disease and permit early intervention to potentially prevent pain, joint destruction and long-term disability, are highly desirable.